Therapeutic formulation for reduced drug side effects

ABSTRACT

The present invention provides drug therapy formulations for reducing the side effects associated with a therapeutic. In some embodiments, the present invention provides a reduction in sleep- and diet-related side effects associated with a therapeutic.

The present patent application is a continuation of U.S. patentapplication Ser. No. 13/093,662, filed on Apr. 25, 2011. Thisapplication also claims priority to provisional patent application Ser.No. 61/327,486, filed Apr. 23, 2010 and provisional patent applicationSer. No. 61/369,338 filed Jul. 30, 2010 which is herein incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention provides drug therapy formulations for reducingthe side effects associated with a therapeutic. In some embodiments, thepresent invention provides a reduction in sleep- and diet-related sideeffects associated with a therapeutic.

BACKGROUND

Drug side effects, including difficulty sleeping, loss of appetite, andabdominal pain, are a significant medical issue. Insomnia, difficultyfalling asleep, or difficulty remaining asleep can result in problemsleepiness, which impairs the health, quality of life and safety ofthose affected. Appetite disorders, such as loss of appetite, can causereduced energy, health, quality of life, and can cause additionaldownstream nutritional deficiencies. Abdominal pain can greatly reducethe quality of life for a patient, and greatly reduce compliance with atherapy regimen. Drug side effects often become more pronounced as drugdosages are increased to achieve longer lasting benefits. As a result,there is a need for therapies which achieve long lasting without theassociated side effects.

For example, attention deficit hyperactive disorder (ADHD) is commonlytreated with stimulants (e.g. norepinephrine reuptake inhibitors (e.g.amphetamines, methylphenidate, etc.)). In order to provide sufficienttherapeutic benefit throughout the day, a large dose morning dose iscommonly administered. Such large doses of stimulants are frequentlyassociated with significant side effects, including insomnia, abdominalpain, and loss of appetite. Children, who commonly suffer from ADHD, areparticularly susceptible to disruption of sleep and/or eating habits andthe additional downstream consequences thereof.

SUMMARY OF THE INVENTION

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a stimulant pharmacologic agent (e.g., agent fortreatment of ADHD or other psychiatric conditions) and a non-stimulantpharmacologic agent for treatment of ADHD (e.g., agent for treatment ofADHD or other psychiatric conditions), wherein the stimulantpharmacologic agent and the non-stimulant pharmacologic agent areformulated for release according to separate schedules. In someembodiments, the stimulant pharmacologic agent is formulated to beginrelease upon administration to a subject. In some embodiments, thestimulant pharmacologic agent is formulated to release over the courseof 0.15 (or less) to 6 hours (e.g., 0.15-6 hours, 0.1-5 hours, 0.15-2hours, 0.15-3 hours, 0.15-4 hours, 0.5-6 hours, etc.), although theinvention is not limited to this particular range. In some embodiments,all or a portion of the stimulant pharmaceutical agent is coated forenteric release. In some embodiments, the non-stimulant pharmacologicagent is formulated to release over the course of 0.15 to 14 (e.g.,0.15-14 hours, 0.3-14 hours, 0.3-12 hours, 0.5-10 hours, 0.5-14 hours,0.15-8 hours, etc.), although the invention is not limited to thisparticular range. In some embodiments, the non-stimulant pharmacologicagent is formulated to begin release upon administration to a subject.In some embodiments, the non-stimulant pharmacologic agent is formulatedfor delayed release. In some embodiments, delayed release comprisesrelease beginning 3 to 6 hours after administration to a subject. Insome embodiments, all or a portion of the non-stimulant pharmaceuticalagent is coated for enteric release. In some such embodiments, after anenteric coating is removed, the non-stimulant is immediately released.In some embodiments, a pharmaceutical composition further comprises anagent to reduce abdominal pain. In some embodiments, the agent to reduceabdominal pain is coated for enteric release. In some embodiments, theagent to reduce abdominal pain comprises peppermint oil.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a stimulant pharmacologic agent for treatment ofADHD, wherein the stimulant pharmacologic agent is provided in ananoparticulate formulation (e.g. for enhanced bioavailability, fastaction, for controlled release, etc.). In some embodiments, the presentinvention provides a pharmaceutical composition comprising anon-stimulant pharmacologic agent for treatment of ADHD, wherein thenon-stimulant pharmacologic agent is provided in a nanoparticulateformulation (e.g. for enhanced bioavailability, for controlled release,etc.). In some embodiments, the present invention provides apharmaceutical composition comprising a stimulant pharmacologic agentfor treatment of ADHD and a non-stimulant pharmacologic agent fortreatment of ADHD, wherein the stimulant pharmacologic agent is providedin a nanoparticulate formulation, wherein the non-stimulantpharmacologic agent is provided in a nanoparticulate formulation, orwherein both the stimulant pharmacologic agent and non-stimulantpharmacologic agent are provided in a nanoparticulate formulation, andwherein the stimulant pharmacologic agent and the non-stimulantpharmacologic agent are formulated for release according to separateschedules. In one or more pharmacologic agents administered in ananoparticulate formulation are further formulated for administrationvia other formulation methods described herein (e.g. co-administration,enteric coating, controlled release, delayed release, immediate release,etc.). In some embodiments, a stimulant pharmacologic agent and/ornon-stimulant pharmacologic agent is complexed to one or more compoundscomprising a nanoparticle (e.g. to enhance bioavailability, to provideslower release of therapeutic, etc.). In some embodiments, a stimulantpharmacologic agents and/or non-stimulant pharmacologic agents areencapsulated within nanoparticles. It is contemplated that use ofnanoparticulate formulations permits further reduction in the dosage ofone or more active agents to achieve an efficacious dose with fewer orreduced side effects.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a first pharmacologic agent (e.g., stimulant) anda second pharmaceutical agent, wherein the first pharmaceutical agent isformulated as a nanoparticulate and the second pharmaceutical agent isnot formulated as a nanoparticulate. In some embodiments, the firstpharmacologic agent is a stimulant and the second pharmaceutical agentis a non-stimulant. In some embodiments, the first pharmacologic agentis a stimulant and the second pharmaceutical agent is a stimulant. Insome embodiments, the first pharmacologic agent is a non-stimulant andthe second pharmaceutical agent is a non-stimulant. In some embodiments,the first pharmacologic agent and the second pharmaceutical agent arethe same agents (e.g., same pharmaceutical compounds). In someembodiments, the first pharmacologic agent and the second pharmaceuticalagent are formulated differently (e.g., nanoparticulate formulation,slow-release formulation, etc.).

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a first pharmaceutical formulation and a secondpharmaceutical formulation, wherein the first pharmaceutical formulationcomprises one or more pharmaceutical agents formulated as ananoparticulate, and the a second pharmaceutical formulation comprisesone or more pharmaceutical agents formulated for slow-release. In someembodiments, the first pharmaceutical formulation and secondpharmaceutical formulation comprise the same pharmaceutical agents. Insome embodiments, the first pharmaceutical formulation and secondpharmaceutical formulation comprise the different pharmaceutical agents.In some embodiments, the first pharmaceutical formulation comprises oneor more stimulant pharmaceuticals. In some embodiments, the firstpharmaceutical formulation comprises one or more non-stimulantpharmaceuticals. In some embodiments, the second pharmaceuticalformulation comprises one or more stimulant pharmaceuticals. In someembodiments, the second pharmaceutical formulation comprises one or morenon-stimulant pharmaceuticals. In some embodiments, the pharmaceuticalagents in the first formulation are formulated for rapid-release uponadministration to a subject. In some embodiments, the pharmaceuticalagents in the second formulation are formulated for slow-release uponadministration to a subject.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a stimulant pharmaceutical agent formulated as ananoparticulate. In some embodiments, the formulation permits fastaction of the stimulant (e.g., biological activity in less than 15minutes, less than 10 minutes, less than 5 minutes, less than 2 minutes)and/or such that activity (and associated side effects, such assleeplessness) are diminished after a desirable period of time (e.g.,before, for example, 10 hours, 8 hours, 6 hours, or 4 hours afteradministration).

In some embodiments, the present invention provides nanoparticlecompositions comprising one or more pharmaceutical agents (e.g.,stimulant, non-stimulant, etc.). In some embodiments, pharmaceuticalnanoparticulates have a diameter (e.g., mean diameter) of less thanabout 10 μm (e.g., <10 μm, <5 μm, <2 μm, <1 μm, <500 nm, <200 nm, <100nm, <50 nm, <20 nm, <10 nm, etc.). In some embodiments, a plurality ofpharmaceutical nanoparticulates have a mean diameter of less than about10 μm (e.g., <10 μm, <5 μm, <2 μm, <1 μm, <500 nm, <200 nm, <100 nm, <50nm, <20 nm, <10 nm, etc.). In some embodiments, pharmaceuticalnanoparticulates have a diameter (e.g., mean diameter) of about 500 nm.In some embodiments, pharmaceutical nanoparticulates have a diameter(e.g., mean diameter) of about 400 nm. In some embodiments,pharmaceutical nanoparticulates have a diameter (e.g., mean diameter) ofabout 300 nm. In some embodiments, pharmaceutical nanoparticulates havea diameter (e.g., mean diameter) of about 200 nm. In some embodiments,pharmaceutical nanoparticulates have a diameter (e.g., mean diameter) ofabout 100 nm. In some embodiments, pharmaceutical nanoparticulates havea diameter (e.g., mean diameter) of about 100-500 nm.

In some embodiments, methods are provided for the production ofpharmaceutical nanoparticles. In some embodiments, pharmaceuticalnanoparticles are produced through one or more steps, including, but notlimited to milling and drying. In some embodiments, milling comprisesroller milling, spindle milling, or any suitable alternative (e.g.,other form of milling, alternative to milling, etc.). In someembodiments, milling of one or more pharmaceutical agents is performedin the presence of one or more solvents (e.g., milling vehicles). Insome embodiments, suitable solvents for milling minimize salvation ofthe pharmaceutical agent(s). In some embodiments, suitable solvents formilling are volatile. In some embodiments, suitable solvents for millinginclude, but are not limited to ethyl acetate, methylene chloride,hexanes, and cyclomethicone. Methods of making nanoparticulatecompositions are described in U.S. Pat. No. 5,518,187 for “Method ofGrinding Pharmaceutical Substances:” U.S. Pat. No. 5,718,388 for“Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No.5,862,999 for “Method of Grinding Pharmaceutical Substances;” U.S. Pat.No. 5,665,331 for “Co-Microprecipitation of NanoparticulatePharmaceutical Agents with Crystal Growth Modifiers;” U.S. Pat. No.5,662,883 for “Co-Microprecipitation of Nanoparticulate PharmaceuticalAgents with Crystal Growth Modifiers;” U.S. Pat. No. 5,560,932 for“Microprecipitation of Nanoparticulate Pharmaceutical Agents;” U.S. Pat.No. 5,543,133 for “Process of Preparing X-Ray Contrast CompositionsContaining Nanoparticles;” U.S. Pat. No. 5,534,270 for “Method ofPreparing Stable Drug Nanoparticles;” U.S. Pat. No. 5,510,118 for“Process of Preparing Therapeutic Compositions ContainingNanoparticles;” and U.S. Pat. No. 5,470,583 for “Method of PreparingNanoparticle Compositions Containing Charged Phospholipids to ReduceAggregation.” all of which are specifically incorporated by reference.In some embodiments, drying of a pharmaceutical composition of thepresent invention is performed by any suitable method (e.g., air drying,vacuum drying, lyophilization, etc.). In some embodiments, milling andor drying is followed by one or more additional steps including but notlimited to sonication.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising an agent to deter abuse of said pharmaceuticalcomposition. In some embodiments, an agent to deter abuse comprises anasal and/or muscosal irritant, polymer composition, and/or emeticcompound.

In some embodiments, the stimulant pharmaceutical agent is an agent thatincreases the levels of dopamine or norepinephrine in a treated subject.In some embodiments, the non-stimulant pharmaceutical agent is an α2adrenergic agonist. Stimulant pharmacologic agents include, but are notlimited to, any one or more of amphetamines (e.g.,(±)-1-phenylpropan-2-amine), lisdexamphetamines (e.g.,N-[(1S)-1-methyl-2-phenylethyl]-L-lysinamide), methylphenidates (e.g.,methyl phenyl(piperidin-2-yl)acetate), dexmethylphenidates (e.g.,(R,R)-(+)-Methyl 2-phenyl-2-(2-piperidyl) acetate), and dexamphetamines(e.g., (5)-1-phenylpropan-2-amine), or derivatives thereof. In someembodiments, the stimulant pharmacologic agent is selected fromamphetamines (e.g. Adderall XR, Adderall, etc.), lisdexamphetamines(e.g. Vyvanse, etc.), methylphenidates (e.g. Concerta, Ritalin. RitalinLA, Metadate CD, Metadate ER, etc.), dexmethylphenidates (e.g. Focalin,Focalin XR, etc.), and dexamphetamines (e.g. Dexedrine). In someembodiments, the non-stimulant pharmacologic agents include, but are notlimited to, Atomoxetine((3R)—N-methyl-3-(2-methylphenoxy)-3-phenyl-propan-1-amine;(R)—N-methyl-3-phenyl-3-(o-tolyloxy) propan-1-amine). Guanfacine(N-(diaminomethylidene)-2-(2,6-dichlorophenyl) acetamide), and Clonidine(N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine) or derivativesthereof. In some embodiments, the non-stimulant pharmacologic agent isselected from Atomoxetine (e.g. Strattera, etc.), Guanfacine (e.g.Intuniv, etc.). Clonidine, etc.

In some embodiments, the present invention provides a method oftreating, preventing, or ameliorating signs or symptoms of a disease orcondition in a subject. To illustrate aspects of the invention, theremaining description focuses on ADHD (attention deficit hyperactivitydisorder). However, it should be understood that the invention is notlimited to this particular condition. In some embodiments, the presentinvention provides treatment and/or symptom reduction for: ADHD, one ormore symptoms of ADHD, ADHD-like conditions, psychiatric conditions,conditions presenting one or more symptoms of ADHD, attention deficitdisorder (ADD), bipolar disorder, autism, seizure disorders, etc. Insome embodiments, the methods comprising administering to a subjectsuffering from ADHD a combination therapeutic agent comprising astimulant pharmacologic agent and a non-stimulant pharmacologic agent,wherein the stimulant pharmacologic agent and the non-stimulantpharmacologic agent are formulated for release according to separateschedules, and wherein administration of the combination therapeuticagent. Such embodiments provide effective relief of symptoms of ADHDwhile minimizing or avoiding undesired side-effects. In someembodiments, the combination therapeutic agent provides effective reliefof symptoms of ADHD using lower doses of the stimulant pharmacologicagent and/or the non-stimulant pharmacologic agent than when thestimulant pharmacologic agent or the non-stimulant pharmacologic agentare used alone to treat ADHD (i.e., the dose administered is lower thanthe normal recommended dose for a particular subject, taking intoaccount age, size, gender, or other factors). In some embodiments, thecombination therapeutic agent provides effective relief of symptoms ofADHD with fewer or reduced side effects from the stimulant pharmacologicagent and/or the non-stimulant pharmacologic agent than when thestimulant pharmacologic agent or the non-stimulant pharmacologic agentare used alone to treat ADHD. In some embodiments, the combinationtherapeutic agent provides effective relief of symptoms of ADHD forlonger duration than when the stimulant pharmacologic agent or thenon-stimulant pharmacologic agent are used alone to treat ADHD. In someembodiments, the stimulant pharmacologic agent is formulated to beginrelease upon administration to a subject. In some embodiments, thestimulant pharmacologic agent is formulated to release over the courseof 0.5 to 6 hours, although other ranges may be used, as desired. Insome embodiments, the non-stimulant pharmacologic agent is formulated torelease over the course of 3 to 12 hours, although other ranges may beused, as desired. In some embodiments, the non-stimulant pharmacologicagent is formulated to begin release upon administration to a subject.In some embodiments, the non-stimulant pharmacologic agent is formulatedfor delayed release. In some embodiments, the delayed release comprisesrelease beginning 3 to 6 hours after administration to a subject,although other ranges may be used, as desired. In some embodiments, thesubject is a child (e.g., a human child under the age of 18, 16, 14, 12,10, 8, 6, etc.). In some embodiments, the combination therapeutic agentprovides effective relief of symptoms of ADHD for 8 to 16 hours. Sideeffects, such as problems with sleep or appetite are reduced oreliminated in the later hours of the day upon a morning administrationof the agents.

In some embodiments, the present invention provides a method oftreating, preventing, or ameliorating signs or symptoms of a disease orcondition in a subject by administering a pharmaceutical composition tothe subject. In some embodiments, the pharmaceutical agent comprises afirst formulation and a second formulation. In some embodiments, thefirst formulation comprises a nanoparticulate of one or morepharmaceutical agents. In some embodiments, the first formulationcomprises one or more pharmaceutical agents and one or morenon-pharmaceutical compositions. In some embodiments, the firstformulation is configured for rapid-release of one or morepharmaceutical agents upon administration to a subject. In someembodiments, the second formulation comprises one or more pharmaceuticalagents. In some embodiments, the second formulation comprises one ormore pharmaceutical agents and one or more non-pharmaceuticalcompositions. In some embodiments, the second formulation is configuredfor slow-release of one or more pharmaceutical agents uponadministration to a subject. In some embodiments, administration of afirst formulation and a second formulation reduces side effects relatedto one or more pharmaceutical agents administered to a subject (e.g.,pharmaceutical agents in the first formulation, pharmaceutical agents inthe second formulation, pharmaceutical agents in both formulations).

In some embodiments, pharmaceutical compositions comprisingnanoparticulate formulations and/or non-nanoparticulate formulationsareutilized in solid or liquid dosage formulations, such as liquiddispersions, gels, aerosols, ointments, creams, controlled releaseformulations, fast melt formulations, lyophilized formulations, tablets,capsules. rapid-release formulations, delayed release formulations,extended release formulations, pulsatile release formulations, mixedimmediate release and controlled release formulations, etc.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a nanoparticulate formulation of I-amphetamineand d-amphetamine. In some embodiments, a pharmaceutical compositioncomprises a nanoparticulate formulation of Adderall. In someembodiments, the mean nanoparticle diameter of the nanoparticulateformulation is less than or approximately 500 nm. In some embodiments,the mean nanoparticle diameter of the nanoparticulate formulation isless than or approximately 250 nm.

In some embodiments, the present invention provides method of treatingADHD (or a similar psychiatric condition or a condition exhibitingsimilar symptoms) in a subject by administering a pharmaceuticalcomposition comprising a nanoparticulate formulation of I-amphetamineand d-amphetamine. In some embodiments, the present invention providesmethod of treating ADHD (or a similar psychiatric condition or acondition exhibiting similar symptoms) in a subject by administering apharmaceutical composition comprising a nanoparticulate formulation ofAdderall. In some embodiments, the present invention provides method oftreating ADHD (or a similar psychiatric condition or a conditionexhibiting similar symptoms) in a subject by co-administering: (a) apharmaceutical composition comprising a nanoparticulate formulation ofI-amphetamine and d-amphetamine, and (b) a second pharmaceutical agentto the subject. In some embodiments, the present invention providesmethod of treating ADHD (or a similar psuchiatric condition or acondition exhibiting similar symptoms) in a subject by co-administering:(a) a pharmaceutical composition comprising a nanoparticulateformulation of Adderall, and (b) a second pharmaceutical agent to thesubject. In some embodiments, the second pharmaceutical agent isformulated for delayed release. In some embodiments, the secondpharmaceutical agent is coated for enteric release. In some embodiments,the second pharmaceutical agent is a non-stimulant. In some embodiments,the non-stimulant is selected from Atomoxetinc, Guanfacine, andClonidine. In some embodiments, the second pharmaceutical agent is astimulant.

In some embodiments, the present invention provides a method forproducing a nanoparticulate formulation of I-amphetamine andd-amphetamine comprising: (a) forming a mixture of I-amphetamine,d-amphetamine, and one or more vehicles: (b) milling said mixture; and(c) drying said mixture. In some embodiments, the present inventionprovides a method for producing a nanoparticulate formulation ofAdderall comprising: (a) forming a mixture of Adderall and one or morevehicles: (b) milling said mixture; and (c) drying said mixture. In someembodiments, the nanoparticles produced have a mean nanoparticlediameter of less than 500 nm. In some embodiments, the nanoparticlesproduced have a mean nanoparticle diameter of less than 250 nm.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a first nanoparticulate formulation and a secondnon-nanoparticulate formulation, wherein the nanoparticulate formulationcomprises one or more stimulants and the non-nanoparticulate formulationcomprises one or more non-stimulant pharmaceutical agents. In someembodiments, the one or more stimulants comprise 1-amphetamine andd-amphetamine. In some embodiments, the one or more stimulants comprisesAdderall. In some embodiments, the mean nanoparticle diameter of thenanoparticulate formulation is less than 500 nm. In some embodiments,the mean nanoparticle diameter of the nanoparticulate formulation isless than 250 nm. In some embodiments, one of the one or morenon-stimulants and selected from Atomoxetine, Guanfacine, and Clonidine

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows laser scattering particle size distribution analysis ofamphetamine salts prior to milling.

FIG. 2 shows laser scattering particle size distribution analysis ofamphetamine in ethyl acetate, 0.5% oleic acid, and cyclohexane.

FIG. 3 shows photomicrograph of amphetamine in ethyl acetate, 0.5% oleicacid, and cyclohexane.

FIG. 4 shows laser scattering particle size distribution analysis ofamphetamine 0.5% oleic acid and cyclohexane after 30 minutes of milling.

FIG. 5 shows photomicrograph of amphetamine in 0.5% oleic acid andcyclohexane after 30 minutes of milling.

FIG. 6 shows laser scattering particle size distribution analysis ofamphetamine 0.5% oleic acid and cyclohexane after 60 minutes of milling.

FIG. 7 shows photomicrograph of amphetamine in 0.5% oleic acid andcyclohexane after 60 minutes of milling.

FIG. 8 shows laser scattering particle size distribution analysis ofamphetamine 0.5% oleic acid and cyclohexane after 120 minutes ofmilling.

FIG. 9 shows photomicrograph of amphetamine in 0.5% oleic acid andcyclohexane after 120 minutes of milling.

FIG. 10 shows laser scattering particle size distribution analysis ofamphetamine 0.5% oleic acid and cyclohexane after 240 minutes ofmilling.

FIG. 11 shows photomicrograph of amphetamine in 0.5% oleic acid andcyclohexane after 240 minutes of milling.

FIG. 12 shows laser scattering particle size distribution analysis ofamphetamine 0.5% Sedefos 75 and cyclohexane after 240 minutes ofmilling.

FIG. 13 shows photomicrograph of amphetamine in Sedefos 75 andcyclohexane after 240 minutes of milling.

FIG. 14 shows laser scattering particle size distribution analysis ofamphetamine in ethanol after 40 hours of milling.

FIG. 15 shows photomicrograph of amphetamine in Sedefos 75 andcyclohexane after 40 hours of milling.

FIG. 16 shows laser scattering particle size distribution analysis ofamphetamine in ethanol after 40 hours of milling: before drying (mediansize=170 nm), dried under vacuum and 10 min. sonication (mediansize=2.91 μm), and dried under vacuum and 30 sec. sonication (mediansize=1.63 μm).

FIG. 17 shows laser scattering particle size distribution analysis ofamphetamine in ethanol after 40 hours of milling, before and afterlyophilization with PVP cryoprotectant.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides drug therapy formulations (e.g.,nanoparticulate formulations, rapid-release formulations,rapid-clearance formulations, delayed release formulations, mixedimmediate release and controlled release formulations, etc.). In someembodiments, provided herein are pharmaceutical formulations forreducing the side effects associated with a therapeutic (e.g., stimulant(e.g., Adderall)). In some embodiments, the present invention provides areduction in sleep- and diet-related side effects associated with atherapeutic (e.g., stimulant (e.g., Adderall)). In some embodiments, thepresent invention provides drug formulation (e.g. nanoparticulateformulation) for enhanced benefit (e.g., rapid release, rapid clearance,rapid onset of therapeutic effect, reducing the side effects, etc.) of atherapeutic (e.g., stimulant (e.g., Adderall)). In some embodiments, thepresent invention provides combination drug therapy for prolonging thebenefit and/or reducing the side effects of a therapeutic throughco-administration with a second therapeutic. In some embodiments, thepresent invention provides a reduction in sleep- and diet-related sideeffects associated with a first therapeutic through co-administrationwith a time-released second therapeutic. In some embodiments, thepresent invention provides formulations (e.g. nanoparticulateformulation) of one or more therapeutics which allows therapeuticbenefit with reduced dosage, thereby reducing side effects (e.g. sleep-and diet-related side effects). In some embodiments, the presentinvention provides formulations (e.g. nanoparticulate formulation) whichprovide enhanced bioavailability, thereby reducing associated sideeffects (e.g. sleep- and diet-related side effects). In someembodiments, the present invention provides formulations (e.g.nanoparticulate formulation) which provide rapid bioavailability. Insome embodiments, the present invention provides formulations (e.g.nanoparticulate formulation) which provide rapid clearance from theblood (e.g., thereby reducing associated side effects (e.g. sleep- anddiet-related side effects)).

In some embodiments, the present invention provides a combinationtherapy whereby two synergistic pharmacological agents areco-administered to provide prolonged benefit to the patient whilereducing side effects associated with one or either individual agent. Insome embodiments, co-administration allows reduced dose of one or bothagents relative to the amount that would be administered as a singleagent therapy. In some embodiments, one or both agents are formulated(e.g. nanopaticle formulation) to provide an additional basis forlowered dosage. In some embodiments, reduced dose of one or bothco-administered agents provides a reduction in associated side effects(e.g. insomnia, loss of appetite, abdominal pain, etc.). In someembodiments, one agent is administered as a nanoparticulate to providerapid bioavailability and/or rapid clearance of the agent.

In some embodiments, the present invention provides administration ofone or more pharmaceutical agents (e.g., stimulant (e.g., Adderall)) ina nanoparticulate formulation. In some embodiments, formulation of theone or more pharmaceutical agents (e.g., stimulant (e.g., Adderall)) ina nanoparticulate provides one or more advantages overnon-nanoparticlate formulation (e.g., rapid release, rapid bloodclearance, reduced side-effects, lower dosage, enhanced bioavailability,etc.). In some embodiments, all the active agents in a pharmaceuticalcomposition are provided in nanoparticulate formulation. In someembodiments, administration as a nanoparticulate allows a similarbenefit (e.g. duration of treatment, effectiveness of symptom reduction,etc.) as conventional formulations with reduced dose of the therapeuticagent (e.g., stimulant (e.g., Adderall)). In some embodiments, reducingthe dose of the therapeutic agent (e.g., stimulant (e.g.,Adderall))reduces negative side effects (e.g. insomnia, loss ofappetite, abdominal pain, etc.) associated therewith (e.g. associatedwith large doses (e.g. large doses required for prolonging duration oftherapeutic benefit). In some embodiments, rapid release of thetherapeutic agent (e.g., stimulant (e.g., Adderall)) reduces theassociated side effects and/or the required dose. In some embodiments,rapid blood clearance of the therapeutic agent (e.g., stimulant (e.g.,Adderall)) reduces the associated side effects.

In some embodiments, one or more pharmaceutical agents are provided inboth a nanoparticulate formulation and non-nanoparticulate formulation(e.g., convention formulation, delayed-release formulation, entericallycoated, etc.). In some embodiments, providing one or more agents in twodifferent formulations formulations (e.g., nanoparticulate andnon-nanoparticulate) provides enhanced bioavailability, reduced sideeffects, prolonged effect, reduced dosage, etc. In some embodiments, asingle pharmaceutical agent (e.g.: a stimulant (e.g., Adderall)) isprovided in both a nanoparticulate formulation and non-nanoparticulateformulation (e.g., convention formulation, delayed-release formulation,enterically coated, etc.). In some embodiments, providing apharmaceutical agent in two different formulations (e.g.,nanoparticulate and non-nanoparticulate) provides enhancedbioavailability, reduced side effects, prolonged effect, reduced dosage,etc.

In some embodiments, the present invention provides co-administration ofa first agent with a second agent. In some embodiments, one or bothagents are formulated as nanoparticulates. In some embodiments, thepresent invention provides co-administration of a first agent with atime-released second agent. In some embodiments, the first agent is alsotime released. In some embodiments, the first agent (e.g., stimulant(e.g., Adderall)) is timed to release early in the treatment course(e.g., first agent is in nanoparticulate). In some embodiments, thefirst agent is formulated (e.g., nanoparticulate) to be cleared from theblood early in the treatment course. In some embodiments, a first agentis formulated with one or more additional pharmaceutical and/ornon-pharmaceutical agents. In some embodiments, the second agent istimed to release late in the treatment course. In some embodiments, thesecond agent in timed to release throughout the treatment course. Insome embodiments, administration of the second agent with the firstagent allows a similar benefit (e.g. duration of treatment,effectiveness of symptom reduction, etc.) from treatment with reduceddose of the first agent. In some embodiments, reducing the dose of thefirst agent reduces negative side effects (e.g. insomnia, loss ofappetite, abdominal pain, etc.) associated with the first agent (e.g.associated with large doses (e.g. large doses required for prolongingduration of the benefit of the first agent). In some embodiments, rapidrelease of the first agent reduces the associated side effects and/orthe required dose. In some embodiments, rapid blood clearance of thefirst agent reduces the associated side effects. In some embodiments,administration of the second agent with the first agent allows a similarbenefit (e.g. duration of treatment) from treatment with reduced dose ofthe second agent. In some embodiments, reducing the dose of the secondagent reduces negative side effects (e.g. insomnia, loss of appetite,abdominal pain, etc.) associated with the second agent (e.g. associatedwith large doses (e.g. large doses required for prolonging duration ofthe benefit of the second agent). In some embodiments, a lower dose ofthe first agent at an early stage in the treatment course causes thefirst agent to be substantially metabolized during the later portion ofthe treatment course such that its active dosage does not exhibitunwanted side effects. In such embodiments, the second agent is activein the later portion of the treatment course to provide or significantlycontribute to the therapeutic benefit-without the associated negativeeffects of the first agent. In some embodiments, nanoparticulateformulation of one or more agents reduces side effects associated withthose agents (e.g., due to rapid release and/or rapid clearance ofnanoparticulate formulated agents).

In some embodiments a first pharmacologic agent and a secondpharmacologic agent provide treatment of the same disorder, disease,condition, and/or symptoms thereof. In some embodiments, first andsecond agents treat the same disorder, disease, condition, and/orsymptoms thereof through different pharmacologic mechanisms. In someembodiments, the differing mechanisms allow for prolonged reduction insymptoms over administration of a single agent. In some embodiments, thediffering mechanisms allow for reducing the total dose of one or bothpharmacological agents. In some embodiments, the differing mechanismshelp reduce side effects associated with one or both agents (e.g.insomnia, abdominal pain, and/or loss of appetite). In some embodiments,reduction in dose of one or both pharmacological agents helps reduceside effects associated with one or both agents.

In some embodiments, the present invention provides co-administration ofa first stimulant pharmaceutical with a second non-stimulantpharmaceutical. In some embodiments, one or both of the first stimulantpharmaceutical and second non-stimulant pharmaceutical are nanoparticleformulated. In some embodiments, the present invention providesco-administration of a first stimulant pharmaceutical (e.g.norepinephrine reuptake inhibitor (e.g. amphetamines, methylphenidate,etc.)) with a second non-stimulant pharmaceutical (e.g. alpha adrenergicagonist (e.g. guanfacine, clonidine, etc.) for the treatment ofattention deficit hyperactive disorder (ADHD). In some embodiments, astimulant and non-stimulant are co-administered to provide an extendedduration of effective treatment of symptoms without increasing the doseof either agent. In some embodiments, a stimulant and non-stimulant areco-administered to provide an extended duration of effective treatmentof symptoms without significant side effects (e.g. insomnia, appetiteloss, abdominal pain). In some embodiments, co-administration of astimulant agent and non-stimulant agent provides extended effectivetreatment of ADHD (e.g. >8 hours, >10 hours, >12 hours, >14 hours, >16hours, up to 24 hours) without side effects associated with large dosesof stimulants. In some embodiments, co-administration of a stimulantagent and non-stimulant agent provides the same duration of symptomrelief as a high dose stimulant-only treatment, using reduced dosage ofstimulant and with reduced stimulant side effects (e.g. reducedinsomnia, reduced appetite loss, reduced abdominal pain, etc.). In someembodiments, co-administration of a stimulant agent and non-stimulantagent provides extended duration of symptom relief over stimulant-onlytreatment (e.g. additional 2 hours of reduced symptoms, additional 4hours of reduced symptoms, additional 6 hours of reduced symptoms,additional 8 hours of reduced symptoms) without additional stimulantside effects (e.g. insomnia, appetite loss, abdominal pain, etc.).

In some embodiments, the present invention provides timed releaseco-administration of a first stimulant pharmaceutical (e.g.norepinephrine reuptake inhibitor (e.g. amphetamines (e.g., Adderall),methylphenidate, etc.)) with a second non-stimulant pharmaceutical (e.g.alpha adrenergic agonist (e.g. guanfacine, clonidine, etc.)) for thetreatment of ADHD. In some embodiments, a first stimulant pharmaceuticalis formulated for immediate release, providing a subject with reducedsymptoms beginning early in the treatment time course (e.g. within 10minutes, within 30 minutes, within 1 hour). In some embodiments, a firststimulant pharmaceutical is formulated to last for several hours (e.g. 3hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours). In someembodiments, a first stimulant pharmaceutical is formulated (e.g., in ananoparticulate) for rapid release and/or clearance (e.g., peak bloodconcentration in <15 minutes). In some embodiments, a secondnon-stimulant pharmaceutical is formulated for delayed release,providing a subject with reduced symptoms beginning midway through thetreatment time course (e.g. beginning at approximately 3 hours, 4 hours,5 hours, 6 hours, 7 hours) and lasting for several hours (e.g. 3 hours,4 hours, 5 hours, 6 hours, 7 hours, 8 hours). In some embodiments, asecond non-stimulant pharmaceutical is formulated for slow release,providing a subject with reduced symptoms (e.g. mild reduction insymptoms) beginning early in the treatment time course (e.g. within 10minutes, within 30 minutes, within 1 hour) and providing a low dosagereleased over multiple hours (e.g. 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, etc.). In someembodiments, slow-release or delayed-release of the second non-stimulantpharmaceutical agent extends the effective reduction of ADHD symptoms ofthe first stimulant pharmaceutical agent, without an increase in dose ofthe stimulant. In some embodiments, slow-release or delayed-release ofthe second non-stimulant pharmaceutical agent extends the effectivereduction of ADHD symptoms of the first stimulant pharmaceutical agent,using a lower dose of the stimulant. In some embodiments, slow-releaseor delayed-release of the second non-stimulant pharmaceutical agentextends the effective reduction of ADHD symptoms of the first stimulantpharmaceutical agent, without stimulant-related side effects (e.g.without significant stimulant-related side effects.

In some embodiments, the present invention provides combination therapyfor the treatment of pediatric ADHD. In some embodiments, the presentinvention provides timed release co-administration of a first stimulantpharmaceutical (e.g. norepinephrine reuptake inhibitor (e.g.amphetamines, methylphenidate, etc.)) with a second non-stimulantpharmaceutical (e.g. alpha adrenergic agonist (e.g. guanfacine,clonidine, etc.)) for the treatment of pediatric ADHD (e.g. patientsunder 25, under 22, under 18, under 16, etc.). In some embodiments,child patients present difficulties in compliance with scheduledadministration of pharmaceutical treatment. In some embodiments, theschool day and/or other childhood-related factors (e.g. desire not totake medicine, desire not to take medicine in front of friends,difficulty remembering to take medicine, etc.) makes administration of asingle pharmaceutical dose in the morning the preferred method oftreatment for increasing therapy compliance. In some embodiments,traditional stimulant therapies require a large dose of stimulant(e.g, >10 mg, >20 mg, >50 mg, etc.) to provide benefit (e.g. reducedADHD symptoms, including, but not limited to, ease of distraction, lossof attention to details, forgetfulness, loss of focus, boredom, learningdisabilities, difficulty completing projects, problems with listening,daydreaming, confusion, slow movement, difficulties processinginformation, difficulties following instructions, fidgeting, excessivetalking, restlessness, excessive motion, impatience, and outbursts)throughout the desired course (e.g. the entire school day, school dayplus afterschool activities, >8 hours, >10 hours, >12 hours, etc.).Large doses of stimulant used in traditional stimulant regimes result insignificant side effects such as insomnia, abdominal pain, and loss ofappetite that carry over into the later part of the day where theybecome life disruptive for the subject and those around the subject.Insomnia, abdominal pain, and loss of appetite have significant impacton a child's health and quality of life. In some embodiments, thepresent invention provides time-released co-administration of astimulant and non-stimulant in a single dose (e.g. a single dose takenat the beginning of the day or before school). In some embodiments, thepresent invention provides timed release co-administration of a firststimulant pharmaceutical (e.g. norepinephrine reuptake inhibitor (e.g.amphetamines (e.g., Adderall), methylphenidate, etc.)) with a secondnon-stimulant pharmaceutical (e.g. alpha adrenergic agonist (e.g.guanfacine, clonidine, etc.)) for full-day treatment of pediatric ADHD(e.g. the entire school day, school day plus afterschool activities, >8hours, >10 hours, >12 hours, etc.). In some embodiments,co-administration of stimulant and non-stimulant provides extendedreduction of symptoms ADHD (e.g. the entire school day, school day plusafterschool activities, >8 hours, >10 hours, >12 hours, etc.) withoutdetrimental side effects (e.g. insomnia, appetite loss, abdominal pain,etc.). In some embodiments, co-administration of stimulant andnon-stimulant provides extended reduction of ADHD symptoms withoutsignificant detrimental side effects (e.g. insomnia, appetite loss,abdominal pain, etc.). In some embodiments, co-administration ofstimulant and non-stimulant provides extended reduction of ADHD symptomswith significantly reduced detrimental side effects (e.g. insomnia,appetite loss, abdominal pain, etc.).

In some embodiments, pharmaceutical agents of the present inventioncontain additional agents to control side effects (e.g. insomnia,appetite loss, abdominal pain, etc.). In some embodiments, peppermintoil is included with a pharmaceutical agent to reduce abdominal painassociated with one or more pharmaceutical agents (e.g. stimulant agent,non-stimulant agent, etc.). In some embodiments, peppermint oil isincluded with a pharmaceutical agent to reduce abdominal pain associatedwith high doses of one or more pharmaceutical agents.

In some embodiments, stimulant pharmaceuticals for use with the presentinvention include amphetamines (e.g. Adderall XR, Adderall, etc.),lisdexamphetamine (e.g. Vyvanse, etc.), methylphenidate (e.g. Concerta.Ritalin, Ritalin LA, Metadate CD, Metadate ER, etc.), dexmethylphenidate(e.g. Focalin, Focalin XR, etc.), and dexamphetamine (e.g. Dexedrine).Those of skill in the will recognize that this list is not limiting andrecognize additional stimulant pharmaceuticals which will find use withembodiments of the present invention. In some embodiments, non-stimulantpharmaceuticals for use with the present invention include Atomoxetine(e.g. Strattera etc.), Guanfacine (e.g. Intuniv, etc.), Clonidine, etc.Those of skill in the will recognize that this list is not limiting andrecognize additional non-stimulant pharmaceuticals which will find usewith embodiments of the present invention.

In some embodiments, the present invention provides nanoparticulateformulations of pharmaceutical agents (e.g., a stimulant (e.g.,Adderall)) for treatment of ADHD. In some embodiments, embodiments ofthe present invention (e.g., co-administration, nanoparticulateformulation, etc.) provide enhanced benefit at a standard does, reducedside effects at a standard does (e.g., 10 mg Adderall, 1 mg guanfacine,etc.), standard benefit at a reduced does (e.g., with reduced sideeffects due to reduced dose), enhanced benefit at a reduced does (e.g.,with reduced side effects due to reduced dose), etc. In someembodiments, the present invention provides nanoparticulate formulationsof Adderall at doses of less than 100 mg/day (e.g., <50 mg/day, <40mg/day, <30 mg/day, <20 mg/day, <10 mg/day, <5 mg/day, etc.). In someembodiments, a single dose of Adderall is given each day (e.g., 10 mg,<10 mg). In some embodiments, multiple doses (e.g., 2, 3, 4, 5, 6, ormore) of Adderall are given each day. In some embodiments, individualdoes contain 10 or less mg/does (e.g., 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5mg, 4 mg, 3 mg, 2 mg, 1 mg). In some embodiments, standard benefit(e.g., reduced ADHD symptoms) is achieved with a reduced dose ofAdderall (e.g., <40 mg/day, <30 mg/day, <20 mg/day, <10 mg/day, <5mg/day, etc.). In some embodiments, a single reduced dose (e.g., 9 mg, 8mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg) is given each day.

In some embodiments, nanoparticulate formulation of a therapeutic agent(e.g., stimulant (e.g., Adderall) allows for reduction in stimulant doseby as much as 75% (e.g. >10%, >25%, >50%, etc.) when compared toconventional modes of administration. In some embodiments,nanoparticulate formulation allows for reduced dosage (e.g., 9 mg/dose,8 mg/dose, 7 mg/dose, 6 mg/dose, 5 mg/dose, 4 mg/dose, 3 mg/dose, 2mg/dose, 1 mg/dose, or less). In some embodiments, nanoparticulateformulation of a therapeutic agent (e.g., stimulant (e.g., Adderall)provides enhanced bioavailability by as much as 100-fold(e.g, >1.1l-fold . . . old 1.2-fold . . . 0.5-fold . . . 2-fold . . .0.5-fold . . . 10-fold . . . 20-fold . . . 50-fold . . . 100-fold, etc.)when compared to conventional modes of administration. In someembodiments, nanoparticulate formulation speeds the rate at which apharmaceutical agent (e.g., a stimulant (e.g., Adderall) becomesbioavailable by as much as 100-fold (e.g. >1.1-fold . . . 1.2-fold . . .1.5-fold . . . 2-fold . . . 5-fold . . . 10-fold . . . 20-fold . . .50-fold . . . 100-fold, etc.) when compared to conventional modes ofadministration. In some embodiments, nanoparticulate formulation speedsthe rate at which a pharmaceutical agent (e.g., a stimulant (e.g.,Adderall) is cleared from the blood by as much as 100-fold(e.g. >1.1-fold . . . 1.2-fold . . . 1.5-fold . . . 2-fold . . . 5-fold. . . 10-fold . . . 20-fold . . . 50-fold . . . 100-fold, etc.) whencompared to conventional modes of administration.

In some embodiments, co-administration of stimulant and non-stimulantusing formulations of the present invention allows for reduction instimulant dose by as much as 75% (e.g, >10%, >25%, >50%, etc.) whencompared to stimulant-only treatment. In some embodiments,co-administration of stimulant and non-stimulant using formulations ofthe present invention allows for reduction in stimulant dose by 10-50%(e.g. 10%, 20%, 30%, 40%, 50%) when compared to stimulant-onlytreatment. In some embodiments, co-administration of stimulant andnon-stimulant using formulations of the present invention allows forreduction in non-stimulant dose by as much as 75%(e.g, >10%, >25%, >50%, etc.) when compared to non-stimulant-onlytreatment. In some embodiments, co-administration of stimulant andnon-stimulant using formulations of the present invention allows forreduction in non-stimulant dose by 10-50% (e.g. 10%, 20%, 30%, 40%, 50%)when compared to non-stimulant-only treatment.

In some embodiments, the present invention provides compositions andmethods for treatment and/or symptom reduction of attention deficitdisorder (ADD), attention deficit hyperactive disorder (ADHD), adultADD, adult ADHD, pediatric ADD, pediatric ADHD, and related conditionsand/or disorders. All embodiments of the invention described herein canbe applied to the above conditions and/or disorders. When used for theabove purposes, said pharmaceutical compound may be administered via anydesired oral, parenateral, topical, intervenous, transmucosal, and/orinhalation routes. The pharmaceutical compound may be administered inthe form of a composition which is formulated with a pharmaceuticallyacceptable carrier and optional excipients, flavors, adjuvants, etc. inaccordance with good pharmaceutical practice.

In some embodiments of the present invention, compositions areadministered to a patient alone or in combination with other therapies,pharmaceuticals, supplements, and/or a specified diet, or inpharmaceutical compositions where it is mixed with excipient(s) or otherpharmaceutically acceptable carriers. In one embodiment of the presentinvention. the pharmaceutically acceptable carrier is pharmaceuticallyinert. In another embodiment of the present invention, compositions(e.g. co-administrations of stimulant and non-stimulant) may beadministered alone to individuals suffering from ADHD.

Depending on the goal of administration (e.g. severity of condition,duration of treatment, etc.), compositions (e.g. co-administrations ofstimulant and non-stimulant) may be formulated and administeredsystemically or locally. Techniques for formulation and administrationmay be found in the latest edition of “Remington's PharmaceuticalSciences” (Mack Publishing Co. Easton Pa.). Suitable routes may, forexample, include oral or transmucosal administration; as well asparenteral delivery, including intramuscular, subcutaneous,intramedullary, intrathecal, intraventricular, intravenous,intraperitoneal, or intranasal administration.

In some embodiments, compositions (e.g. nanoparticulat drugformulations, co-administrations of stimulant and non-stimulant, etc.)are in the form of a solid, semi-solid or liquid dosage form: such astablet, capsule, orally-disintegrating tablets, pill, powder,suppository, solution, elixir, syrup, suspension, cream, lozenge, pasteand spray containing the first and second agents formulatedappropriately to provide the desired time-release profile. As thoseskilled in the art would recognize, depending on the chosen route ofadministration, the composition form is selected.

In some embodiments, the pharmaceutical composition (e.g.,nanoparticulate, multiple co-administered compounds, etc.) areadministered in single or multiple doses. In preferred embodiments, thepharmaceutical compound is administered in a single dose. In someembodiments, a single oral pill or capsule is provided containing thefirst and second agents. In some preferred embodiments, a capsule isused containing the first agent in a form that permits early release andthe second agent in a form that permits later release. The particularroute of administration and the dosage regimen will be determined by oneof skill, in keeping with the condition of the individual to be treatedand said individual's response to the treatment. In some embodiments, asingle oral pill or capsule is provided containing a nanoparticulateformulation of one or more therapeutic agents (e.g., a stimulant (e.g.,Adderall).

In some embodiments, substituents of a composition of the presentinvention may be adjusted to provide desirable solubility or othercharacteristics for administration by any suitable technique.

In some embodiments, pharmaceutical agents of the present invention areformulated for slow release, delayed release, immediate release, timedrelease, or combinations thereof. In some embodiments, a pharmaceuticalagent, or portions of a pharmaceutical agent, is enterically coated toprotect the agent or agents from dissolving in the stomach. In someembodiments, enterically coated pharmaceuticals dissolve, releasingpharmaceutical agents, upon reaching a desired location (e.g., the smallintestine). In some embodiments, enteric coating of an agent delaysrelease of the agent for several hours (e.g. 3 hours, 4 hour, 5 hours, 6hours, 7 hours, etc.). In some embodiments, an enterically coated agentmay be formulated for immediate release upon loss of the enteric coatingor for slow release (e.g. over the course of hours). In someembodiments, an enterically coated agent may be formulated for immediaterelease upon loss of the enteric coating.

The present invention also provides pharmaceutical compositions in aunit dosage form for administration to a subject, comprisingpharmaceutical compounds (e.g. stimulant and non-stimulant) and one ormore nontoxic pharmaceutically acceptable carriers, adjuvants orvehicles. The amount of the active ingredients (e.g. stimulant andnon-stimulant) that may be combined with such materials to produce asingle dosage form will vary depending upon various factors, asindicated above. A variety of materials can be used as carriers,adjuvants, and vehicles in the composition of the invention, asavailable in the pharmaceutical art.

In some embodiments, the present invention provides nanoparticulateformulations of one or more pharmacologic agents. In some embodiments, asingle pharmacologic agent is provided in a nanoparticulate formulation.In some embodiments, the present invention provides nanoparticulateformulations comprising one or more pharmacologic agents (e.g., astimulant (e.g., Adderall)) for the treatment of ADHD. In someembodiments, the present invention provides nanoparticulate formulationscomprising one or more stimulant pharmacologic agents. In someembodiments, the present invention provides nanoparticulate formulationscomprising one or more non-stimulant pharmacologic agents. In someembodiments, the present invention provides nanoparticulate formulationscomprising one or more stimulant pharmacologic agents and one or morenon-stimulant pharmacologic agents. In some embodiments, methods ofmaking nanoparticulate formulations comprising pharmacologic agents, anduses and methods of administration thereof are understood in the art(See, e.g., U.S. Pat. Nos. 5,145,648; 5,641,515; 6,592,903; 5,585,108;5,518,738; 6,375,986; 7,198,795; 5,518,187; 5,862,999; 5,718,388;5,510,118; herein incorporated by reference in their entireties). Insome embodiments, nanoparticulate formulation provides pharmaceuticalcompositions with enhanced bioavailability. In some embodiments,nanoparticulate formulation provides pharmaceutical compositions withdesirable release characteristics (e.g. controlled release, delayedrelease, slow release, etc.). In some embodiments, nanoparticulateformulation provides pharmaceutical compositions with rapidbioavailability (e.g., <1 hour, <30 minutes, <15 minutes, <5 minutes, <1minute, <30 seconds, <10 seconds, etc.). In some embodiments,nanoparticulate formulation provides pharmaceutical compositions withrapid blood clearance, for example, the majority of the pharmaceuticalcomposition is cleared from the blood within 1 hour (e.g., <1 hour, <30minutes, <15 minutes, <5 minutes, <1 minute, <30 seconds, <10 seconds,etc.). In some embodiments, nanoparticulate formulation of pharmacologicagents provides enhanced therapeutic benefit. In some embodiments,reduced dosage of a nanoparticulate formulation of one or morepharmacologic agents provides similar therapeutic benefit toconventional formulations at conventional dosages. In some embodiments,nanoparticulate formulation of one or more pharmacologic agents providesreduced side effects (e.g., insomnia, appetite loss, abdominal pain,etc.). In some embodiments, nanoparticulate formulation of one or morepharmacologic agents provides reduced side effects (e.g. insomnia,appetite loss, abdominal pain, etc.) because lower doses are used toachieve the same benefit as conventional formulations. In someembodiments, nanoparticulate formulation of one or more pharmacologicagents provides reduced side effects (e.g. insomnia, appetite loss,abdominal pain, etc.) because of the rapidity of bioavailabilitycompared to conventional formulations. In some embodiments,nanoparticulate formulation of one or more pharmacologic agents providesreduced side effects (e.g. insomnia, appetite loss, abdominal pain,etc.) because of the rapidity of blood clearance compared toconventional formulations. In some embodiments, nanoparticulateformulation of one or more pharmacologic agents provides reduced sideeffects (e.g. insomnia, appetite loss, abdominal pain, etc.) because thecontrolled release properties of nanoparticulate formulation providemore optimal levels of pharmacologic agents circulating in thebloodstream of a subject, although the present invention is not limitedto any particular mechanism of action and an understanding of themechanism of action is not necessary to practice the present invention.In some embodiments, nanoparticulate formulation of stimulant and/ornon-stimulant allows for reduction in dose or stimulant and/ornon-stimulant by as much as 75% (e.g, >10%, >25%, >50%, etc.) whencompared to conventional treatment. In some embodiments, nanoparticulateformulation of stimulant and/or non-stimulant allows for reduction instimulant dose by 10-50% (e.g. 10%, 20%, 30%, 40%, 50%) when compared toconventional treatment.

In some embodiments, pharmaceutical nanoparticulates (e.g., containingAdderall) have a diameter (e.g., mean diameter) of less than about 10 μm(e.g., <10 μm, <5 μm, <2 m, <1 μm, <500 nm, <200 nm, <100 nm, <50 nm,<20 nm, <10 nm, etc.). In some embodiments, pharmaceuticalnanoparticulates (e.g., containing Adderall) have a diameter (e.g., meandiameter) of about 450-550 nm (e.g., about 500 nm). In some embodiments,pharmaceutical nanoparticulates (e.g., containing Adderall) have adiameter (e.g., mean diameter) of about 350-450 nm (e.g., about 400 nm).In some embodiments, pharmaceutical nanoparticulates (e.g., containingAdderall) have a diameter (e.g., mean diameter) of about 250-350 nm(e.g., about 300 nm). In some embodiments, pharmaceuticalnanoparticulates (e.g., containing Adderall) have a diameter (e.g., meandiameter) of about 150-250 nm (e.g., about 200 nm). In some embodiments,pharmaceutical nanoparticulates (e.g., containing Adderall) have adiameter (e.g., mean diameter) of about 50-150 nm (e.g., about 100 nm).In some embodiments, pharmaceutical nanoparticulates (e.g., containingAdderall) have a diameter (e.g., mean diameter) of about 25-75 nm (e.g.,about 50 nm).

EXPERIMENTAL Example 1

Pediatric ADHD Co-Administration Regimen

Patient dosing is determined on an individual patient basis taking intoaccount the age, size, and weight of the patient; severity of thecondition; and empirical response to the treatment. Exemplary stimulantand non-stimulant dose and time-release regimens within the scope of thepresent invention as provided below. One of skill in the art wouldunderstand that the co-administration therapy can be altered, forgeneral practice or for specific patients, in terms of dose, timing ofrelease, and rate of release for either agent.

Exemplary regimen A. Patient is administered 10 mg of amphetamine salts(e.g. Dexamphetamine) and 1 mg guanfacine in a single dose in the earlypart of the day (e.g. morning). The amphetamine salts are formulated forimmediate release, and the guanfacine is formulated for delayed release.Although the present invention is not limited to any particularmechanism of action and an understanding of the mechanism of action isnot necessary to practice the present invention, it is contemplated thatin this configuration the Dexamphetamine provides a rapid reduction insymptoms continuing through the early hours of the time-course (e.g.morning), and the guanfacine extends the reduction of symptomsthroughout the later portion of the time course (e.g. afternoon);therefore, the combination reduces symptoms over the entire time-coursewith reduced side effects caused by multiple doses.

Exemplary regimen B. Patient is administered 9 mg of amphetamine salts(e.g. Dexamphetamine) and 0.9 mg guanfacine (10% reduction in totaldaily dose) in a single dose in the early part of the day (e.g.morning). The amphetamine salts are formulated for immediate releaseover approximately 5 hours, and the guanfacine is formulated for releasebeginning after a 4 hours and continuing for approximately 5 hours.Although the present invention is not limited to any particularmechanism of action and an understanding of the mechanism of action isnot necessary to practice the present invention, it is contemplated thatin this configuration the Dexamphetamine provides a rapid reduction insymptoms continuing through the early hours of the time-course (e.g.morning), and the guanfacine extends the reduction of symptomsthroughout the later portion of the time course (e.g. afternoon).

Exemplary regimen C. Patient is administered 9 mg of amphetamine salts(e.g. Dexamphetamine) and 0.9 mg guanfacine (10% reduction in totaldaily dose) in a single dose in the early part of the day (e.g.morning). The amphetamine salts are formulated for release by twoseparate mechanisms, 5 mg are formulated for immediate release, 4 mg arecoated for enteric release (e.g. release after approximately 4 hours).The guanfacine is formulated for release beginning after 4 hours andcontinuing for approximately 5 hours. Although the present invention isnot limited to any particular mechanism of action and an understandingof the mechanism of action is not necessary to practice the presentinvention, it is contemplated that in this configuration theDexamphetamine provides a rapid reduction in symptoms continuing throughthe early hours of the time-course, which is supplemented by the entericrelease several hours later. The guanfacine extends the reduction ofsymptoms throughout the later portion of the time course (e.g.afternoon) without undesired side effects.

Exemplary regimen D. Patient is administered 9 mg of amphetamine salts(e.g. Dexamphetamine) and 0.9 mg guanfacine (10% reduction in totaldaily dose) in a single dose in the early part of the day (e.g.morning). The amphetamine salts are formulated for release by twoseparate mechanisms, 5 mg are formulated for immediate release, 4 mg arecoated for enteric release (e.g. release after approximately 4 hours).The guanfacine is coated for enteric release beginning afterapproximately 4 hours and formulated for slow release continuing overthe course of several hours (e.g. 4 hours, 5 hours, 6 hours, 7 hours, 8hours, 9 hours, 10 hours, etc.). Although the present invention is notlimited to any particular mechanism of action and an understanding ofthe mechanism of action is not necessary to practice the presentinvention, it is contemplated that in this configuration theDexamphetamine provides a rapid reduction in symptoms continuing throughthe early hours of the time-course, which is supplemented by the entericrelease several hours later. The guanfacine extends the reduction ofsymptoms throughout the late portion of the time course withoutundesired side effects.

In any of the above regimens, peppermint oil may be included in theformulation, either as immediate release, or, for example, may beenterically coated (e.g., alone with other components) for immediaterelease after several hours to target both the timing and location ofabdominal pain side effects associated with some therapeutic agents.

Example 2

Nanoparticulate Formulation Dosing

Exemplary stimulant and/or non-stimulant dose and time-release regimens,for use with nanoparticulate formulation, within the scope of thepresent invention is provided below. One of skill in the art wouldunderstand that the regimens can be altered, for general practice or forspecific patients, in terms of dose, formulation, combinations, timingof release, and rate of release for one or more agents.

Exemplary regimen A. Patient is administered 10 mg of a nanoparticulateformulation of amphetamine salts (e.g. Dexamphetamine) in a single dosein the early part of the day (e.g. morning). The amphetamine salts areformulated for immediate release over approximately 5 hours. Althoughthe present invention is not limited to any particular mechanism ofaction and an understanding of the mechanism of action is not necessaryto practice the present invention, it is contemplated that in thisconfiguration the nanoparticulate formulation provides enhancedbioavailability of Dexamphetamine, thereby allowing a reduced dose,resulting in reduce side effects.

Exemplary regimen B. Patient is administered 6 mg of a nanoparticulateformulation of amphetamine salts (e.g. Dexamphetamine) and 0.9 mgguanfacine (10% reduction in total daily dose) in a single dose in theearly part of the day (e.g. morning). The amphetamine salts areformulated for immediate release over approximately 5 hours, and theguanfacine is formulated for release beginning after a 4 hours andcontinuing for approximately 5 hours. Although the present invention isnot limited to any particular mechanism of action and an understandingof the mechanism of action is not necessary to practice the presentinvention, it is contemplated that in this configuration thenanoparticulate formulation of Dexamphetamine provides a rapid reductionin symptoms, at a reduced dosage, continuing through the early hours ofthe time-course (e.g. morning), and the guanfacine extends the reductionof symptoms throughout the later portion of the time course (e.g.afternoon).

Exemplary regimen C. Patient is administered 9 mg of a nanoparticulateformulation of amphetamine salts (e.g. Dexamphetamine) in a single dosein the early part of the day (e.g. morning). The nanoparticulateamphetamine salts are formulated for release by two separate mechanisms,5 mg are formulated for immediate release, 4 mg are coated for entericrelease (e.g. release after approximately 4 hours). The guanfacine isformulated for release beginning after 4 hours and continuing forapproximately 5 hours. Although the present invention is not limited toany particular mechanism of action and an understanding of the mechanismof action is not necessary to practice the present invention, it iscontemplated that in this configuration the Dexamphetamine provides arapid reduction in symptoms continuing through the early hours of thetime-course, which is supplemented by the enteric release several hourslater. It is contemplated that in this configuration the nanoparticulateformulation provides enhanced bioavailability of Dexamphetamine, therebyallowing a reduced dose, resulting in reduce side effects.

Exemplary regimen D. Patient is administered 6 mg of a nanoparticulateformulation of amphetamine salts amphetamine salts (e.g. Dexamphetamine)and 0.6 mg a nanoparticulate formulation of guanfacine in a single dosein the early part of the day (e.g. morning). The nanoparticulateamphetamine salts are formulated for release by two separate mechanisms.3.5 mg are formulated for immediate release. 2.5 mg are coated forenteric release (e.g. release after approximately 4 hours). Thenanoparticulate guanfacine is formulated for release beginning after 4hours and continuing for approximately 5 hours. Although the presentinvention is not limited to any particular mechanism of action and anunderstanding of the mechanism of action is not necessary to practicethe present invention, it is contemplated that in this configuration theDexamphetamine provides a rapid reduction in symptoms continuing throughthe early hours of the time-course, which is supplemented by the entericrelease several hours later. The guanfacine extends the reduction ofsymptoms throughout the later portion of the time course (e.g.afternoon) without undesired side effects. It is contemplated that inthis configuration the nanoparticulate formulation provides enhancedbioavailability, thereby allowing a reduced dose, resulting in reduceside effects.

Exemplary regimen E. Patient is administered 7 mg of a nanoparticulateformulation of amphetamine salts (e.g. Dexamphetamine) and 0.7 mg of ananoparticulate formulation of guanfacine (10% reduction in total dailydose) in a single dose in the early part of the day (e.g. morning). Thenanoparticulate amphetamine salts are formulated for release by twoseparate mechanisms. 4 mg are formulated for immediate release. 3 mg arecoated for enteric release (e.g. release after approximately 4 hours).The guanfacine is coated for enteric release beginning afterapproximately 4 hours and formulated for slow release continuing overthe course of several hours (e.g. 4 hours, 5 hours, 6 hours, 7 hours, 8hours, 9 hours, 10 hours, etc.). Although the present invention is notlimited to any particular mechanism of action and an understanding ofthe mechanism of action is not necessary to practice the presentinvention, it is contemplated that in this configuration theDexamphetamine provides a rapid reduction in symptoms continuing throughthe early hours of the time-course, which is supplemented by the entericrelease several hours later. The guanfacine extends the reduction ofsymptoms throughout the late portion of the time course withoutundesired side effects. It is contemplated that in this configurationthe nanoparticulate formulation provides enhanced bioavailability,thereby allowing a reduced dose, resulting in reduce side effects.

In any of the above regimens, peppermint oil may be included in theformulation, either as immediate release, or, for example, may beenterically coated (e.g., alone with other components) for immediaterelease after several hours to target both the timing and location ofabdominal pain side effects associated with some therapeutic agents.

Example 3

Deterrent of Abuse

Stimulants, such as amphetamines and methylphenidate, are widely abusedas prescription products. The stimulants elevate the levels of dopamineas well as norepinephrine. Non-stimulants on the other hand act only byincreasing the levels of norepinephrine. Drugs that elevate dopamine(e.g. amphetamine, methamphetamine, cocaine) make people euphoric. Dueto this pharmacologic effect, stimulant drugs are abused whereasnon-stimulant drugs typically are not. According to the NationalInstitutes on Drug Abuse (part of the NIH) stimulants are abused forboth “performance enhancement” and recreational purposes. For theformer, they suppress appetite and facilitate weight loss. The euphoriceffects of stimulants usually occur when they are crushed and thensnorted or injected. Some abusers dissolve the tablets in water andinject the mixture.

In some embodiments, the present invention provides compositions,systems, and methods to deter the abuse of stimulant drugs in thetreatment of ADHD. In some embodiments, the present invention providescompositions and methods to deter subjects from taking unadvisable,off-prescription, and/or unintended dosages of pharmaceuticals of thepresent invention. In some embodiments, the present invention providescompositions and methods to deter subjects from taking and/oradministering pharmaceuticals of the present invention via unintended,off-prescription, and/or unadvisable routes (e.g. intravenously,snorting, etc.). In some embodiments, the present invention includes anabuse deterrent formulation for reducing the potential for one or moreof a) parenteral abuse, b) inhalation (e.g., intranasal abuse), and/orc) oral abuse of a drug, for satisfaction of a physical or psychologicaldependence. In some embodiments, the invention comprises combiningstimulant and non-stimulant drugs in a once daily dosing regimen, wherethe stimulant dose is reduced (e.g. reduced by 10-50%). In someembodiments, the invention provides stimulant and non-stimulant drugs ina tamper resistant formulation wherein the stimulant is combined with apolymer (e.g. polyethylene oxide, polyvinyl alcohol, hydroxypropylmethyl cellulose, carbomers, other such pharmaceutical agents, etc.) orsuitable pharmaceutical excipients to form a matrix that will make itdifficult for a person to abuse by dissolving the dosage form in wateror solvent and or snorting or injecting the solution. In someembodiments, the invention provides stimulant and non-stimulant drugscombined with an irritant. In some embodiments, reduction of stimulantdose, combination with an irritant, a formulation that is difficult totamper with, or a combination thereof provides a deterrent to abuse ofcompositions of the present invention.

In some embodiments, a pharmaceutical composition of the presentinvention comprises a surfactant present in sufficient amount to causenasal irritation. In some embodiments, a pharmaceutical composition ofthe present invention comprises an inert excipient in sufficient amountto cause emesis if greater than a prescribed amount included in thetherapeutic composition is ingested. In some embodiments, apharmaceutical composition of the present invention comprises an emeticin sufficient amount to cause emesis if greater than a prescribed amountof the analgesic included in the therapeutic composition is ingested. Insome embodiments, the amount of emetic present in a pharmaceuticalcomposition of the present invention can be tied directly to the amountof drug in the pharmaceutical composition. Thus, by controlling thequantity of the emetic compound in the pharmaceutical composition,emesis can be avoided if normal prescription directions are followed.However, if an overdosage occurs by ingesting more than a prescribedquantity of a drug in a pharmaceutical composition of the presentinvention, the amount of ingested emetic can exceed the threshold amountnecessary to induce emesis.

In some embodiments, the present invention deters inhalation abuse byproviding a pharmaceutical composition which includes one or more mucousmembrane, mucosa or mucosal tissue irritants (collectively referred toas mucous membrane irritants). In one embodiment, suitable mucousmembrane irritants and/or nasal passageway tissue irritants includecompounds that are generally considered pharmaceutically inert, yet caninduce irritation. Such compounds include, but are not limited tosurfactants. In some embodiments, suitable surfactants include sodiumlauryl sulfate, poloxamer, sorbitan monoesters, glyceryl monooleates,etc. Other suitable compounds are believed to be within the knowledge ofa practitioner skilled in the relevant art, and can be found in theHandbook of Pharmaceutical Excipients, 4th Ed. (2003), the entirecontent of which is hereby incorporated by reference. In someembodiments, two or more of the abuse deterrents can be combined intoone composition according to the present invention.

In some embodiments, the present invention incorporates or applies abusedeterrent compositions, dosages, and methods known in the art (U.S. Pat.Nos. 7,510,726; 7,476,402; herein incorporated by reference in theirentireties). In some embodiments, the abuse deterrent compositions andmethods described herein find use with any embodiments of the presentinvention.

Example 4

Nanoparticulate Formulation

In some embodiments, experiments were performed during development ofembodiments of the present invention to produce nanoparticles comprisingpharmaceutical compositions (e.g., mixture of amphetamines) with areduced particle size distribution. Experiments were conducted todecrease the particle size of an amphetamine mixture to a median sizebelow 400 nm. A milling procedure, in which active pharmaceuticalingredients (APIs), were milled together to produce nanoparticles, wasused. Successfully milled API was be loaded into hard gelatin capsulesfor use in a non-GLP in vivo study to compare pharmacokinetics to thecommercially available dosage form. The amphetamine milled was a 3:1 D:Lmixture of amphetamine isomers, obtained by preparing a 1:1 mixture ofamphetamine and the racemic mixture dextroamphetamine. The sulfate saltof each API was used for the project sourced from Johnson-Matthey Plc.

The inherent water solubility of the two amphetamine salts necessitatedmilling in non-aqueous vehicles. Vehicles were identified thatexhibited: 1) minimal solvency for the APIs. and 2) sufficientvolatility to allow for their removal to yield a dry powder of themilled material. Based on these criteria: ethyl acetate, methylenechloride, hexanes, and cyclomethicone were identified as potentialmilling vehicles.

The initial particle size distribution of the mixture was measured usinga Horiba LA-950V2 with a median size of approximately 32 μm (SEE FIG.1). Suspensions at 5% of the 1:1 mixture of amphetamine salts in each ofthe identified vehicles were made, and roller milled in 20 mL glassvials using 0.5 mm YTZ milling media. The vials were rolled on a USStoneware laboratory roller mill with particle size measured after fourand 16 hours of milling. No additives or dispersants were used in theseinitial trials so as not to complicate drying and recovery as tocalculation of yield.

Microscopic analysis revealed that the milling procedure resulted in asize reduction in all milling vehicles, though this was not indicated inthe PSD measurements using the Horiba due to agglomeration of the milledparticles. Additional measurements were made adding 0.1% oleic acid as adispersant to the cyclohexane used as diluent for the measurement,resulting smaller sizes, though still not representative to that seenmicroscopically (See Table 1).

TABLE 1 Roller Milling Results Median Particle Size [μ] Roller MillingPSD 0.1% Oleic acid PSD in in Cyclohexane Cyclohexane 24 hr w/30 minSolvent 4 hr 16 hr 16 hr 24 hr sonic Ethyl Acetate 21.3 26.4 8.7 21.110.4 (300 nm) Methylene 33.7 45.9 12.8  23.6 8.7 Chloride Hexane 13.5 Nosignal No signal 4.1 N/A Cyclomethicone 31.9 17.4 8.2 10.9 18.1  (300nm)

Sonication was applied to the preparations which reduced size further,though not be representative of actual primary particle size observedmicroscopically.

Hexanes presented a particular issue in that the API particles appearedto fuse/heavily agglomerate to the media resulting in a lack ofmeasurable particles, and further work was discontinued using thisvehicle. Some samples did exhibit evidence of a bimodal distributionwith a population at the target range (values in parenthesis in Table1).

To speed the rate of milling, the ethyl acetate and methylene chloridesamples were transferred to spindle milling. In spindle milling, themedia is stirred rather than depending on gravity to move the media asin roller milling, allowing input of a higher level of energy to thegrinding. Some additional particle size reduction was found after twohours of spindle milling, though still not judged representative of thatobserved microscopically. In effort to disperse the observedagglomerates, a higher level of 0.5% oleic acid was tried for the PSDpreparation diluent, but did not provide appreciably better results (SeeTable 2). Graying of the samples was also observed likely due toabrasion of the stainless steel spindle, so this approach was notpursued further.

TABLE 2 Spindle Milling Results Median Particle Size [μ] Spindle MillingPSD 0.1% Oleic acid in PSD 0.5% Oleic acid in Cyclohexane Cyclohexane 2hr w/5 min 2 hr w/5 min Solvent 2 hr sonication sonication Ethyl Acetate10.4 11.1 8.9 Methylene Chloride 17.6 11.6 10.5

To determine if the cause of agglomeration was caused by overgrinding,an investigation was started to determine particle size versus millingtime. Roller milling in ethyl acetate with no milling aid or dispersantwas used, with particle size measured at initial and 30, 60, 120, and240 minutes. From these results, the progression of particle sizereduction was as desired and evidence of overgrinding was not observed(SEE FIGS. 2-11).

Experiments conducted during development of embodiments of the presentinvention indicated that APIs were milling well, but could not bedispersed well enough to accurately measure the primary particle size.Alternate dispersants were investigated to overcome this difficulty.Sedcfos75 (Gattefosse) was identified to provide good dispersion of themilled APIs for particle size measurement (SEE FIGS. 12 and 13).However, the Sedefos was also found to form micelles in ethyl acetate ofsimilar size, especially in the presence of trace water in the ethylacetate, leading to uncertainty of the accuracy of the measurement.During investigations, anhydrous ethanol was found to disperse the APIswell without the addition of any dispersant, and a milling trial wasperformed giving a median size of 200 nm after 40 hr of milling,measured without the addition of any dispersant (SEE FIGS. 14 and 15).The milling was performed at a loading of 5% of the amphetamine mixturein the ethanol.

Upon successfully milling the amphetamines, experiments were conductedto determine an appropriate drying procedure to maintain the milledparticle size. This was tested by redispersing in ethanol and measuringthe resultant particle size. First, ethanol was dried off under vacuum,though this resulted in irreversible particle size growth even withsonification to disperse the particles (SEE FIG. 16). It was nextattempted to lyophilize the milled dispersion. Lyophilization of thestraight suspension was also found to cause an increase in particlesize. However, the addition of 1% PVP K-29/32 to the milled suspensionas a cryoprotectant was found to adequately maintain particle size. Asecond larger batch was milled to be used to produce the test articlecapsules. This batch required 52 hr of milling to eliminate the tail oflarger sized particles. Upon completion of the milling, the suspensionwas harvested and modified with the addition of the PVP K-29/32. Thesuspension was lyophilized at −45° C./0.1 torr with a cycle time ofapproximately 17 hr. Post-lyophilized particle size was measured andfound to be similar to the pre-lyophilized size (SEE FIG. 17).

Twenty size 000 hard gelatin capsules were filled by hand on a 5-placeanalytical balance to a target fill of 11.3-11.5 mg. This target fillweight is the calculated equivalent of 6.3 mg of amphetamine in the freebase form (See Table 3)

TABLE 3 Calculation of Free-Base Equivalent Yield from Total Cake Weight555 mg Lyophilization PVP added pre 135 mg lyophilization AMP sulfatewt. in cake 420 mg Free base AMP sulfate mw 368.49 calculation AMP mw135.2 Salt is 2 AMP:1 H₂SO₄ 270.4/368.49 % free-base in salt 73.38%Free-base target 6.3 mg free-base per capsule Salt equivalent 6.3mg/0.7338 8.59 mg salt Salt % less PVP 420 mg/555 mg 75.68% Fill wt.8.59 mg/0.7568  11.35 mg Salt + PVP

Example 5

Bioanalysis of Nanoparticulates Administered to Subjects

A LC-MS/MS method was developed for the determination of both1-amphetamine and d-amphetamine in mini-pig plasma (sodium heparin)using (d, l)-amphetamine-d6 as an internal standard. Sample volume usedwas 100 μL of mini-pig plasma, with any necessary dilutions performed inblank mini-pig plasma prior to extraction. Sample clean-up consisted ofa liquid-liquid extraction of analyte into methyl tert-butyl ether(MTBE), followed by evaporation of the organic, and reconstitution inmobile phase. The d- and 1-isomers of amphetamine were separated byliquid chromatography on a Chiral-CBH column from Chiral Technologies.An isocratic gradient using a mobile phase consisting of 6% acetonitrilein 10 mM ammonium acetate and 50 μM EDTA at 220 gL/min was used toseparate lamphetamine and d-amphetamine, with retention times ofapproximately 3.6 and 4.6 minutes, respectively, with a total run timeof 10 minutes. A calibration curve was prepared by spiking test compoundinto blank mini-pig plasma with a range from 0.5 ng/mL to 500 ng/mL,timepoints were taken at 15 minutes, 30 minutes, 45 minutes 1 hour, 1.5hours, 3 hours, 6 hours, 8 hours, and 24 hours. Date indicated thatplasma concentrations of d-amphetamine and 1-amphetamine in pig plasmapeaked prior to the 15 minute timepoint and were being cleared over thefirst several time-points (e.g., 1.5 hours). For PK analysis, the drughad lower plasma concentrations for both the d- and 1-forms ofamphetamine. The corresponding PK parameters also reflect thisdifference in lower AUC. PK analysis demonstrated that both the d- andl-forms of amphetamine were rapidly cleared, and indicated that the peakconcentration in plasma occurred prior to the 15 minute time-point. Suchrapid clearance was unexpected.

Although the invention has been described in connection with specificpreferred embodiments, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the described modes for carrying outthe invention that are obvious to those skilled in the relevant fieldsare intended to be within the scope of the following claims.

What is claimed is:
 1. A pharmaceutical composition consisting ofdexamphetamine nanoparticles, wherein the dexamphetamine nanoparticleshave a mean diameter of up to 50 nm, and guanfacine.
 2. Thepharmaceutical composition of 1, wherein the dexamphetaminenanoparticles have a mean diameter of up to 25 nm.
 3. A pharmaceuticalcomposition consisting of: a. a component formulated for rapid releaseconsisting of dexamphetamine nanoparticles wherein the dexamphetaminenanoparticles have a mean diameter of up to 50 nm; and b. componentformulated for delayed release consisting of guanfacine.
 4. Thepharmaceutical composition of 3, wherein the dexamphetaminenanoparticles have a mean diameter of up 25 nm.
 5. A pharmaceuticalcomposition consisting of: a. a component formulated for rapid releaseconsisting of amphetamine nanoparticles wherein the amphetaminenanoparticles consist of levoamphetamine and dexamphetamine, and theamphetamine nanoparticles have a mean diameter of up to 50 nm; and b. acomponent formulated for delayed release consisting of guanfacine. 6.The pharmaceutical composition of claim 5, wherein said amphetaminenanoparticles have a mean diameter of up to 25 nm.